tbuckley/cabot-search huggingface dataset:
NCMP-17. IMPROVEMENT IN CRANIAL NEUROPATHIES FOLLOWING STEREOTACTIC RADIOTHERAPY ALONE FOR SKULL BASE MENINGIOMAS
Authors: Karim Hafazalla, Matthews Lan, Keenan Piper, Preston Carey, Omaditya Khanna, David Andrews, James Evans, Kevin Judy, Christopher Farrell
Journal: Neuro-Oncology (2023)

Abstract Cranial neuropathies are a common presenting symptom in skull base meningiomas. Many of these tumors are not amenable to surgical resection; for these patients, stereotactic radiotherapy (SRT) is a viable option. Our study sought to investigate the efficacy of SRT for improving cranial neuropathies and identify predictors that portend favorable response. A single-institution retrospective analysis was performed for patients with skull base meningiomas causing cranial neuropathies who received SRT as sole treatment from 2001 to 2021. Clinical variables were collected and analyzed for predictors of improvement. Subgroup analysis for each type of cranial neuropathy was also performed. Overall 101 patients were included, of which 51 (50.4%) had an improvement in cranial neuropathy following SRT. There was no difference in gender or age between patients with and without improvement. The most common tumor location was cerebellopontine angle (n=38), followed by cavernous sinus (n=27) and optic canal (n=25). Cranial nerve II was most frequently affected (n=34), followed by VI (n=28) and V (n=27). There was no significant difference in tumor volume, radiation dose, location, or specific cranial nerve affected between patients with and without improvement. Median time to improvement was 8 months (IQR 3-15). In subgroup analysis, patients with optic neuropathy who experienced improvement after SRT were significantly younger (50.7 vs. 60.1 years, p=0.03), while patients with trigeminal neuropathy who experienced improvement were significantly older (69.6 vs. 58.7 years, p=0.03). For patients with extraocular movement neuropathies or vestibulocochlear dysfunction, there were no significant factors associated with improvement. Half of patients with cranial neuropathy from skull base meningiomas experience symptomatic improvement following sole SRT. Age may play a role in predicting improvement, with younger patients more likely to have improved vision and older patients more likely to experience improvement in trigeminal neuropathy.
EPCO-03. A COMPREHENSIVE SINGLE-CELL ATLAS OF SCHWANNOMA REVEALS CONSERVED CELLULAR STATES ACROSS DIFFERENT GENETIC BACKGROUNDS AND ANATOMIC LOCATIONS
Authors: Luis Nicolas Gonzalez Castro, Avishai Gavish, Lillian Bussema, Cyril Neftel, Masashi Nomura, E Antonio Chiocca, Wenya Linda Bi, Omar Arnaout, Frederick Barker, Justin Brown, Justin T Jordan, Anat Stemmer-Rachamimov, Scott R Plotkin, Itay Tirosh, Mario Suva
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Despite being associated with molecular alterations in the NF2 gene, there is limited understanding of the gene expression programs that govern the behavior of schwannomas both in sporadic cases as well as in patients with schwannoma predisposition syndromes, and also with respect to their anatomic location. METHODS We characterized the transcriptional heterogeneity of schwannomas across different genetic backgrounds and anatomic locations at the single-cell level. Tumor samples from patients undergoing resection for symptomatic schwannoma were dissociated and single cells were processed for full-transcript whole transcriptome profiling via Smart-seq2. Our cohort of 22 schwannomas, includes 5 tumors from schwannomatosis patients, 11 tumors from neurofibromatosis type 2 patients, and 6 sporadic tumors – 3 of which had grown after radiation treatment. Anatomically, 12 tumors were excised from cranial nerves (11 vestibular, 1 accessory) and 10 from spinal and other peripheral nerves. RESULTS We profiled 11,373 cells, including 4725 neoplastic cells, 2425 fibroblasts, 1314 T cells, 1258 endothelial cells, 969 myeloid cells, 503 pericytes and 240 Schwann cells. Copy number alteration analyses reveal evidence of intratumoral polyclonality (supporting the hypothesis of multiple sites of origin for a tumor). Using non-negative matrix factorization, we identify 6 distinct transcriptional metaprograms, with gene signatures related to stress, myelin production, antigen presentation, interferon signaling, glycolysis and extracellular matrix. After comparison with a pan-cancer gene expression dataset, we note unique interferon and antigen presentation metaprograms in schwannoma, with the latter being mainly characterized by expression of MHC Class II genes. Overall, we observe conserved expression of these metaprograms across anatomic locations and genetic backgrounds, with the exception of decreased interferon signaling for vestibular tumors. CONCLUSION We provide a comprehensive single-cell characterization of schwannoma spanning diverse genetic and anatomic backgrounds. We describe unique transcriptional metaprograms for antigen presentation and interferon signaling, which might underlie mechanisms for immune evasion.
NCMP-22. FLUDARABINE NEUROTOXICITY IN PATIENTS UNDERGOING CAR T-CELL THERAPY - A REPORT OF 2 CASES
Authors: Yi Li, Jan Drappatz, Megan Mantica
Journal: Neuro-Oncology (2023)

Abstract Fludarabine is a purine analog used in the treatment of chronic lymphocytic leukemia (CLL) and as part of immunosuppressive/lymphodepleting regimens in allogeneic stem cell transplant and chimeric antigen receptor (CAR) T-cell therapy. It induces cellular cytotoxicity through multiple mechanisms, ultimately leading to the inhibition of DNA synthesis. Although myelosuppression is the primary dose-limiting side effect of fludarabine, there have been reported cases of delayed-onset neurological symptoms, such as progressive visual impairments, dementia, ataxia, hemiparesis, quadriparesis, and blindness. These symptoms have been observed in patients receiving fludarabine alone or as part of preconditioning treatments for CAR T-cell therapy. The neurological abnormalities are characterized by leukoencephalopathies and can manifest as posterior reversible encephalopathy (PRES), acute toxic leukoencephalopathy (ATL), or other leukoencephalopathy (OLE). We present two cases of patients who underwent fludarabine conditioning before CAR T-cell therapy, exhibiting late-onset and progressive changes in vision and encephalopathy. These symptoms differ in timing and pattern from the neurotoxicities commonly associated with CAR T-cell therapy. Nonetheless, given the overlapping neurological toxicities seen with both CAR-T cell therapy and fludarabine, it is important to consider implementing thorough screening measures to modify preconditioning fludarabine dose intensity, particularly for patients with advanced disease, renal insufficiency, or other risk factors to limit fludarabine-associated adverse effects.
CTNI-52. SURVIVAL OUTCOMES IN RECURRENT GLIOBLASTOMA (RGBM) PATIENTS TREATED WITH A SINGLE INTRA-TUMORAL ADMINISTRATION OF BIZAXOFUSP, AN IL-4R-TARGETING TOXIN, IN A PHASE IIB TRIAL
Authors: John Sampson, Achal Singh Achrol, Manish Aghi, Krystof Bankiewicz, Martin Bexon, Steven Brem, Andrew Brenner, Sajeel Chowdhary, Melissa Coello, Annick Desjardins, Benjamin Ellingson, John Floyd, Seunggu Han, Santosh Kesari, Yael Mardor, Fahar Merchant, Rosemina Merchant, Dina Randazzo, Michael A Vogelbaum, Frank Vrionis, Eva Wembacher-Schroeder, Minh D To, Miroslaw Zabek, Nicholas Butowski
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Bizaxofusp (MDNA55) is an IL4R-targeting toxin in development for recurrent (r)GBM, a universally fatal disease with mOS of 6-9 months. IL-4R is overexpressed in GBM and surrounding tumor microenvironment, with high expression associated with poor clinical outcome. Method: Efficacy and safety were evaluated in a single-arm, open-label, multi-center Ph2 study using convection-enhanced delivery of Bizaxofusp. The primary endpoint of mOS was compared to results from a blinded eligibility-matched external control arm (ECA). OS was defined as time from relapse to death/censor. IL-4R expression was determined by immunohistochemistry of available archival tumor tissues from both arms. RESULTS Bizaxofusp showed an acceptable safety profile at doses of up to 240 μg. Forty-four subjects were treated with Bizaxofusp per protocol; 81 ECA subjects met the eligibility criteria of the study. The Bizaxofusp group had a significantly longer mOS (12.85 months compared to 7.7 months for ECA; HR, 0.62; 95% CI, 0.42-0.89). Amongst the unmethylated MGMT and high IL-4R sub-groups, subjects treated with Bizaxofusp had significantly longer mOS when compared to the ECA. Eleven patients (25%) treated with Bizaxofusp survived &amp;gt;24 months; 3 patients were still alive (29.9, 32.8 and 40.1 months) at last follow-up. High IL-4R expression was associated with improved survival (mOS, 15.8 versus 9.8 months; HR, 0.7; 95% CI, 0.39-1.46) at all doses. However at high doses (180 μg) subjects with low IL-4R expression had significantly longer survival versus low dose Bizaxofusp (mOS, 15.4 versus 9.1 months; HR, 0.28; 95% CI, 0.09-0.91). CONCLUSION In patients with rGBM, a single treatment of Bizaxofusp resulted in significantly improved OS compared to eligibility-matched ECA. High-dose Bizaxofusp was equally effective irrespective of IL4R expression. A Phase 3 registration trial will use a novel hybrid design with a propensity-matched ECA comprising two-thirds of the control arm, setting a new precedent for GBM clinical trials.
CSIG-30. FUNCTIONAL CHARACTERISATION OF A NOVEL MUTATION IN PRKCA, THE MAJOR DRIVER OF CHORDOID GLIOMAS
Authors: Charlotte Bellamy, Hannah Tovell, Florent Dingli, Stephane Liva, Damarys Loew, Eduard Stefan, Selina Schwaighofer, Alexandra Newton, Marc Sanson, Franck Bielle
Journal: Neuro-Oncology (2023)

Abstract Chordoid gliomas (ChG) are a rare low-grade brain tumour, believed to be derived from Tanycytes. An analysis by the team previously identified a novel mutation present in all ChGs: PRKCA p.D463H. This mutation involves a D463H amino acid substitution at the kinase domain of the Protein kinase C alpha (PKCα) and represents the hallmark of ChG. PKCα is a serine/threonine kinase, that carries out the regulation of various functions in the cell. The aim of the project is to identify novel and biologically relevant PKCα D463H signalling pathways, which will demonstrate the involvement and the role of this mutated kinase in cellular functions implicated in the development of ChGs. The D463H mutation affects a critical residue of the kinase domain of PKCα, suggesting that such change may modify substrate affinity and specificity. Following the purification of the mutated form of PKCα, we have shown it is an inactive kinase, that has a dominant negative effect over the wild type (WT) PKCα. The mutation affects the tertiary structure of the protein, resulting in a more open, unstable protein. Phosphoproteomic analysis of HEK cells overexpressing the mutant protein has shown a global loss of PKCα substrate phosphosites compared to the WT condition. By understanding these changes, integrated with our snRNAseq and bulk RNAseq data of ChGs, we hope to elucidate the mechanism by which the mutation leads to tumorigenesis. Finally, the candidates will be explored in a representative context, by exploring the PKCɑ D463H mutation in primary rat Tanycyte culture and in vivo model. These models will allow us to study the effect of the mutation on cellular processes involved in the development of this rare tumour.
CTNI-43. A PHASE 1/2 STUDY OF LOW DOSE FRACTIONATED RADIATION THERAPY AS A CHEMOPOTENTIATOR OF SALVAGE TEMOZOLOMIDE FOR HIGH-GRADE GLIOMA
Authors: Timothy Lin, Suqi Ke, Chen Hu, Debraj Mukherjee, Jon Weingart, Lawrence Kleinberg, James Huang, Ryan Assadi, Matthias Holdhoff, Stuart Grossman, Mansoor Ahmed, Kristin Redmond
Journal: Neuro-Oncology (2023)

Abstract Cell-survival curves demonstrate low-dose radiation hypersensitivity, with steepest cell kill at 0.3-0.5 Gy/fx. This phase 1/2 study assessed the safety/efficacy of low-dose fractionated radiotherapy (LDFRT) as a chemopotentiator of TMZ in recurrent glioblastoma or anaplastic astrocytoma (AA) patients. Patients with recurrent glioblastoma/AA following standard-of-care therapy, &amp;gt; 12 months from prior RT and &amp;gt;2 months from prior TMZ were eligible for 0.5 Gy RT twice daily x10 fractions with concurrent TMZ (150-200 mg/m2), both delivered in 5 days of a 28-day cycle up to 6 cycles, followed by 6 cycles of adjuvant TMZ. In phase 1, hematologic toxicity was assessed 1 month after initiating therapy. Brain MRIs were obtained every 2 months, or monthly when concerned for progression (defined by RANO criteria). Pseudoprogression consisted of MRI changes irrespective of clinical deterioration/steroid use that stabilized/reversed without oncologic intervention. The primary endpoint, 1-year overall survival (OS), would be considered for future investigation with a lower bound of 80% CI &amp;gt; 28%, chosen from historical data. Secondary endpoints included rates of pseudoprogression and hematologic toxicity. 31 patients were enrolled/analyzed. Grade 3-4 acute hematologic toxicity was observed in 8(27%) patients. Median follow-up was 9.5(range:0.1-66.3) months. Median OS was 9.6(95%CI 7.0-15.4) months. 1-year OS was 34.5%(95%CI 20.9%-57.0%; lower bound of 80%CI = 24.8%). 77% of patients experienced pseudoprogression, with a median time from start of LDFRT of 1.9(95%CI 1.7-4.4) months and median duration of 3.6(95%CI 1.6-Not estimable) months. Patients with pseudoprogression had improved OS vs. those without (N = 6; median 10.6 vs 3.9 months, HR = .12[95%CI .03-.40];P &amp;lt; .01). LDFRT for recurrent glioblastoma/AA was safe. High pseudoprogression rates were observed at low RT doses, with improved OS amongst patients with pseudoprogression. LDFRT with TMZ may elicit low-dose RT hypersensitivity in patients with glioblastoma/AA. Further study is needed to optimally apply this radiobiological property to improve clinical outcomes.
EPCO-41. MICRORNA-MEDIATED DIRECT NEURONAL REPROGRAMMING OF GLIOBLASTOMAS
Authors: Luorongxin Yuan, Kitra Cates, Devi Annamalai, Albert Kim, Andrew Yoo
Journal: Neuro-Oncology (2023)

Abstract Neuron-specific microRNAs miR-9/9* and miR-124 (miR-9/9*-124) are potent neurogenic molecules whose ectopic expression in non-neuronal somatic cells effectively induces direct cell fate conversion into a neuronal fate. Our recent work indicates that the fate transition occurs in distinct steps where miR-9/9*-124 first represses core gene regulatory networks to erase the original non-neuronal cell identity and subsequently activates the neuronal program to confer neuronal fate. Extending these findings, we reason that repression of similar gene regulatory networks by miR-9/9*-124 can also induce fate erasure in cancerous cells using glioblastoma as a paradigm. Glioblastoma multiforme (GBM) is a type of aggressive brain tumor with poor prognosis. Instead of having specific mutation profiles, GBMs present a global genetic network dysregulation which gives rise to a neural stem cell or progenitor cell-like state resembling embryonic neural development. Whereas miR-9/9*-124 plays a key role in inducing mitotic exit and orchestrating neurogenesis during development and neuronal reprogramming, we hypothesize that miR-9/9*-124 will instruct neuronal reprogramming of GBMs. Our results so far demonstrate that miR-9/9*-124 indeed exerts reprogramming activities in patient-derived GBM cell lines. Ectopic expression of miR-9/9*-124 in vitro readily induces GBM cells to exit cell cycle and promotes neuronal identity over time. In GBM intracerebral xenograft mouse model, mice receiving GBM cells overexpressing miR-9/9*-124 were able to survive longer than those with GBMs overexpressing non-specific microRNAs. We are currently carrying out transcriptomic and chromatin accessibility analyses to infer the epigenetic switch as GBM cells are reprogrammed to neurons. Based on these studies, we will further examine whether the GBM cells undergo irreversible fate erasure and are reprogrammed into a stable post-mitotic neuronal state. Our studies will provide insights into the plasticity of GBM fate that can be controlled by microRNAs and the key downstream regulatory nodes underlying fate transition of GBM to permanent post-mitotic state.
MODL-46. RECAPITULATING CELLULAR HETEROGENEITY AND TREATMENT-SPECIFIC EFFECTS THROUGH SINGLE-CELL ANALYSIS OF PATIENT-DERIVED TUMOR SLICE CULTURE MODELS
Authors: Aditya Mohan, John Bassett, Jonathan Jerry, Rushil Yerrabelli, Emily Blandford, Anca Mihalas, John Sampson, Anoop Patel
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Malignant brain tumors are almost universally fatal despite standard-of-care (SOC) therapy with radiation (XRT) and temozolomide (TMZ). Low Grade Glioma (LGG) is a subclass of malignant glioma that can harbor an R132H mutation in Isocitrate Dehydrogenase 1 (IDH1). Extensive clinical trials have explored the clinical utility of IDH1 R132H mutation small molecule inhibitors such as ivosidenib and vorasidenib; however, the direct intracellular and intercellular effects of IDH1 R132H inhibition relative to SOC remain largely unknown. Objective This study examines these issues by developing a novel patient-specific tumor slice culture model to study the effects of both SOC and IDH1 R132H inhibition on IDH1 mutant glioma. Method En-bloc tumor samples from a patient with IDH mutant LGG undergoing surgery were sectioned into 400 um thick slices using a vibratome and cultured on porous microwell inserts for up to 14 days. Tumor slices were then either left untreated or treated with SOC (XRT/TMZ) or ivosidenib and harvested at various time points. Samples were hashed, and single-cell RNA sequencing was performed and analyzed. Result: Patient-derived tumor slice cultures were able to grow and were observed to contain heterogeneous cell populations, including tumor cells, astrocytes, neurons, oligodendrocytes, and microglia. When slice cultures were treated with SOC and ivosidenib treatment, separate tumor subpopulations were shown to be sensitive to either treatment. Furthermore, scRNA analysis revealed unique subpopulations that were insensitive to either treatment. We further demonstrate that slice cultures treated with Ivosidenib enriched for gene signatures related to protein translation and antigen processing. Intriguingly, we find that tumor cultures treated with ivosidenib abrogated the Notch signaling pathways between tumor-tumor and tumor-immune clusters. CONCLUSION Herein, we demonstrate that patient-derived tumor slice cultures are a viable strategy for understanding drug effects and tumor sensitivity to different therapies.
EXTH-23. EFFECT OF EVOGLIPTIN AND TEMOZOLOMIDE COMBINATION THERAPY FOR THE TREATMENT OF GLIOBLASTOMA, <i>IN VITRO AND IN VIVO</i>
Authors: Seung Ho Yang, Keun Soo Lee, Jung Eun Lee
Journal: Neuro-Oncology (2023)

Abstract A recent study showed that high dipeptidyl-peptidase IV (DPP4) expression affects glioma progression. The purpose of this study is to investigate the synergistic effect of a DDP4 inhibitor, evogliptin and temzolomide (TMZ) combination therapy for glioblastoma (GBM) in vitro and in vivo. U87, U252, and A172 cells were treated with 50, 250, and 500 uM TMZ or with 5, 10, and 20 mM evogliptin for 24, 48 and 72 hrs. For in vivo experiment, GBM xenograft models were used. Three groups (n=5 mice) were treated with TMZ(15mg/kg/day), evogliptin (2mg/25g/day), and combination of TMZ and evogliptin via i.p. injection for 4 weeks. For evaluating the relevant mechanism, Affymetrix miRNA arrays are used. The MTT assay revealed that the combination treatment had higher cytotoxicity against U87, U251, and A172 cells than the monotherapy had after 48 and 72-hr treatment. mRNA DDP4 levels were much more decreased after combination administration. The median survival of each group was 43.6, 55.2, 53.2, 65.2, and 71.3 days in the control, evogliptin, TMZ, the first combination therapy with low-dose evogliptin (2mg/25g/day) and TMZ, and the second combination therapy with high-dose evogliptin (10mg/25g/day) and TMZ, respectively. In Affymetrix miRNA arrays, miR-1246, miR-149-3p, miR-3148, miR-4440, miR-4484, miR-4535, miR-6126, miR-6780b-5p, and miR-7110-5p were increased after evogliptin treatment. miR-149-5p, miR-23a-5p, miR-3195, miR-4330, miR-4497, miR-4669, miR-671-3p, and miR-744-5p were decreased. miR-4440 and miR-6780b-5p were also increased following combination therapy. In the TCGA dataset, the survival of glioma patients with low DPP4 expression is longer than that in patients with high DPP4. A DDP4 inhibitor, evoglipin regulates miRNA in GBM cell lines. The combination of evogliptin and TMZ had a moderate effect on the treatment of GBM in vitro and in vivo. miR-4440 and miR-6780b-5p could be associated with inhibiting the proliferation of GBM cells by targeting DPP4.
NCOG-11. PREOPERATIVE NANO SCORE AS A PREDICTOR FOR SURVIVAL IN GLIOBLASTOMA
Authors: Eduard Mendoza Mireles, Hanne Kristin Blakstad, Erlend Skaga, Eirik Helseth, Pål Rønning, Einar Vik-Mo
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Age, molecular features, extent of resection, and adjuvant treatment are well established prognostic factors for patients with glioblastoma. Neurological Assessment in Neuro-Oncology (NANO) Scale was designed as a tool to provide an objective clinician-reported outcome of neurologic and complements the radiological evaluation of the Response Assessment in Neuro-Oncology (RANO) criteria. Despite the generally detrimental prognosis associated with severe new neurological deficits after surgery, a comprehensive understanding of the impact of pre- and postoperative neurological status remains limited. This study explores the potential of the NANO scale to predict survival when applied immediately before and after surgery. METHODS This retrospective study examined adult patients in South-Eastern Norway who underwent resection for IDH wildtype glioblastoma between January 2020 and December 2021. We used Kaplan Meier curve calculate median overall survival and chi-square and log rank test were used to compare groups. RESULTS The study included 187 patients, with a median overall survival was 14.9 months. Patients with a preoperative NANO-score of 0-2 had a median survival of 17.4 months, compared to 11.3 months for patients scoring 3 or more points (p&amp;lt; 0.001). Neither Postoperative NANO scores nor changes in NANO scores in pre- to postoperative score were found to be significant predictors for survival. CONCLUSIONS This study indicates that a low preoperative NANO were predictive for a longer median survival, whereas postoperative NANO scores didn’t show the same impact. Surprisingly, an increase in the postoperative NANO score, indicating new, or worsening of the neurological deficits, didn′t correlate with a shorter median survival.